Bisphenol-C is the strongest bifunctional ER[alpha]-agonist and ER[beta]-antagonist due to magnified halogen bonding

• Published in: PloS one 2021-02, Vol.16 (2), p.e0246583
• Main Authors: Liu, Xiaohui, Suyama, Keitaro, Nose, Takeru, Shimohigashi, Miki, Shimohigashi, Yasuyuki
• Format: Article
• Language: English
• Subjects: Chemical properties; Estrogen; Phenols; Receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0246583

We reported that bisphenol AF (BPAF) works as an agonist for estrogen receptor (ER) ER[alpha] but as an antagonist for ER[beta]. Similar results were observed for bisphenol E analogs (BPE-X) such as BPE-F, BPE-Cl, and BPE-Br, each consisting of a series of a tri-halogenated methyl group CX.sub.3 in the central alkyl moiety. It was demonstrated that the electrostatic halogen bond based on the dispersion force of halogen atoms is a major driving force in the activities of bifunctional ER[alpha]-agonist and ER[beta]-antagonist. Since the chlorine atoms present in bisphenol C (BPC) exist in a [qi]-[qi] conjugated system due to the presence of an adjacent C = C double bond, we intended to prove that BPC is also a bifunctional ER[alpha]-agonist and ER[beta]-antagonist exhibiting greatly enhanced agonist/antagonist activities. BPC was evaluated for its ability to activate ER[alpha] and ER[beta] in the luciferase reporter gene assay using HeLa cells. With high receptor-binding ability to both ERs, BPC was found to be fully active for ER[alpha] but inactive for ER[beta]. BPC's definite antagonist activity in ER[beta] was revealed by its inhibitory activity against 17[beta]-estradiol. Thus, BPC is a bifunctional ER[alpha]-agonist and ER[beta]-antagonist. These agonist/antagonist activities were discovered to be extremely high among series of halogen-containing bisphenol compounds. This comparative structure-activity study revealed that the ascending order of ER[alpha]-agonist and ER[beta]-antagonist activities was BPE-F